(lower)alkoxytetrahydropyranyl ethers and 5&#39;,6&#39;-dihydro-2h-pyran-4&#39;yl ethers of 7beta-methyl-delta4-androstanes

ABSTRACT

THE 4&#39;&#39;-LOWER)ALKOXYTETRAHYDROPYRAN-4&#39;&#39;-YL ETHERS AND 5&#39;&#39;,6&#39;&#39;-DIHYDRO-2H-PYRAN-4&#39;&#39;-YL ETHERS OF 7B-METHYL-$4-ANDROSTANES HAVE HIGH ORAL ANABOLIC ACTIVITIES.

"United States Patent @fice 3,728,336 Patented Apr. 17, 1973 3,728,336(LOWER)ALKOXYTETRAHYDROPYRANYL ETHERS AND 5',6-DlHYDRO-2H-PYRAN- 4'YLETHERS F 7p-METHYL-A -ANDR0- STANES Alexander D. Cross, San Francisco,and John A. Edwards, Los Altos, Calif., assignors to Syntex Corporation,Panama, Republic of Panama No Drawing. Continuation-in-part ofapplications Ser. No. 731,300, May 22, 1968, and Ser. No. 766,321, Oct.9, 1968. This application May 11, 1970, Ser. No. 36,457

Int. Cl. C07c 173/00 U.S. Cl. 260-23955 R 12 Claims ABSTRACT OF THEDISCLOSURE The 4'-(lower)alkoxytetrahydropyran-4'-yl ethers and,6-dihydro-2H-pyran-4'-yl ethers of 7fl-methyl-A -androstanes have highoral anabolic activities.

This is a continuation-in-part of United States patent applications Ser.No. 731,300, filed May 22, 196 8 and Ser. No. 766,321, filed Oct. 9,1968.

This invention relates to novel and useful 4-(lower)alkoxytetrahydropyran-4'-yl ethers and 5',6-dihydro-2H- pyran-4'-ylethers of 7/3-methyl-A -androstanes which can be represented by theformula:

In the above formula,

R is hydrogen or methyl;

R is hydrogen or lower alkyl; and

R is a 4'-(lower)alkoxytetrahydropyran-4'-yl or 5',6'-

dihydro-2H-pyran-4'-yl group.

The compounds represented by Formula I are anabolic agents with afavorable anaboliczandrogenic ratio, also possess anti-estrogenic,anti-gonodatropic, and anti-fibrillatory activities, and can be used inthe same manner as testosterone. These compounds are administered by theusual routes, whether orally or parenterally, either alone or inconjunction with other medicinal agents, or in pharmaceuticallyacceptable, non-toxic compositions formed by the incorporation of any ofthe normally employed excipients.

The terms lower alkyl and derivatives thereof appearing in the abovedefinitions and elsewhere in the instant specification denote alkylgroups containing from 1 to 6 carbon atoms, inclusive, such as methyl,ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, amyl, hexyland the like. 7

The compounds of Formula I can be prepared from the corresponding17fl-hydroxy compounds. The latter are reacted under substantialanhydrous conditions with an excess of4'-(lower)alkoxy-5',6-dihydro-2Hpyran. The hydroxy compounds arereacted, for example, with from about 2 to about 50 or more molecularequivalents of the pyran reagent in the presence of a small amount of anacidic catalyst, such as hydrochloric acid, p-toluenesulfonic acid,boron trichloride etherate, and the like, either alone or together withan inert, organic solvent, such as benzene, diethyl ether, methylenechloride, or the like. The reaction is carried out at a temperatureranging from about 0 C. to about C. (preferably at around roomtemperature, i.e., 25 C.) for about 5 minutes to about 48 hours, thusgiving the corresponding ethers represented by Formula I. In carryingout this reaction, a mixture of the respective 4'-(lower)alkoxytetrahydropyran-4'-yl ethers and 5,6'-dihydro-2l-I-pyran-4'- ylethers are formed. Use of non-hydrocarbon solvents for the reactionmedium, lower catalyst concentrations, and shorter reaction timesincrease the yield of the 4'- (lower)alkoxytetrahydropyran-4'-yloxycompounds. The two reaction products are then separated by conventionalprocedures.

For example, the two reaction products can be separated and purified bycolumn chromatography with neutral alumina, eluting with hexane andhexane-benzene solutions. The fractions containing the compounds areidentified by spectroscopic techniques. The 5',6-dihydro2H- pyran-4-ylethers, being less polar, are eluted first. After fractions containingmixtures of the two products, fractions containing the4-(lower)alkoxytetrahydropyran-4'- yl ethers are obtained. The compoundsare obtained by evaporating the solvents.

Alternatively, the two products can be separated and purified bypreparative thin layer chromatography. The reaction mixture is appliedto a preparative plate containing a phosphor, and the plate is developedwith a hexane-ethyl acetate mixture containing a trace of pyridine. Theplates are dried, and the bands containing the separated products areidentified under ultraviolet light, the silica gel in each zone beingcollected and eluted with tetrahydrofuran. The solvent is evaporated todryness to yield the isolated products.

The 4-(lower)alkoxy-S,6'-dihydro-2H-pyran reactants used to form theethers of this invention can be prepared by well known methods. Forexample, tetrahydro-4-pyrone can be reacted with a primary or secondarylower alkanol under acidic conditions to form the intermediate,4,4'-di(lower)alkoxytetrahydropyran, which upon distillation with anacid, such as toluenesulfonic acid or mesitylenesulfonic acid, yieldsthe 4-(lower)alkoxy-5',6'- dihydro-ZH-pyran product. Such a method isdescribed by Reese et al. I. Am. Chem. Soc. 89, 3367 (1967). The loweralkanol is preferably methanol but it can be other lower alkanols suchas ethanol, propanol, isopropanol, butanol, isobutanol, pentanol, amylalcohol, hexanol, and the like, to form the corresponding pyrans, suchas, for example, 4'-met.hoxy-5', 6r-dihydro=2H-pyran, 4-ethoxy-5',6'-dihydro-2H-pyran, etc.

The 17fi-hydroxy compounds from which the compounds of Formula I areprepared and methods suitable for preparing them have been described inUS. Patents Numbers 3,213,086, 3,262,949, and 3,341,557 and by Zderic eta1. Steroids 81, 432 (1959).

This invention is further illustrated by the following specific butnon-limiting examples.

EXAMPLE 1 To a solution of 1 g. of l7/3-hydroxy-7 3-methylandrost-4-en-3-one and 25 ml. of benzene there is added 2 ml. of4-methoxy-5,6-dihydro-2H-pyran. Next, approximately 5 ml. of the mixtureof benzene and dihydropyran is distilled off to remove moisture, and theremaining mixture is then cooled to room temperature. To the cooledmixture is then added 0.1 g. of p-toluenesulfonic acid, and theresulting reaction mixture is held at room temperature for 72 hours.Following this reaction period, the reaction mixture is washed with anaqueous 5 percent sodium carbonate solution and then with water until aneutral pH is obtained, then dried over anhydrous sodium sulfate andevaporated to dryness. The dry residue is then applied to a hexanesolution to a column of 80 g. of neutral alumina. The column is thencarefully eluted with hexane and hexane-benzene (increasing the benzeneconcentration in steps of percent, i.e. 5 percent, percent, percentbenzene, etc.). The fractions obtained at the various concentrations ofbenzene are collected, and those containing the products are identifiedby spectroscopic techniques. The 5,6'-dihydro-2H-pyran-4-yl ether iseluted first. Following this eluant portions containing both etherproducts, and then fractions containing the4'-methoxytetrahydropyran-4'-yl ether is obtained. The solvents areevaporated to yield the two separated products 175-(5,6-dihydro-2H-pyran-4-yloxy)7[3 methylandrost 4- en-3-one and1715'-(4'rnethoxytetrahydropyran-4'-yloxy)-7fl-methylandrost-4-en-3-one.

EXAMPLE 2 Repeating the procedure of Example 1 but replacing the175-hydroxy-7B-methylandrost-4-en-3-one with17,8-hydroxy-7,8-methylestr-4-en-3-one,17B-hydroxy-175,17a-dimethylandrost-4-en-3-one, 173-hydroxy-7B,l7a-dimethylestr-4-en-3-one,17ot-ethyl-17fl-hydroxy-7[3-methylandrost-4-en-3-one, and17a-ethyl-17,6-hydroxy-7fi-methylestr-4-en-3-one,

yields the corresponding EXAMPLE 3 Repeating the procedure of Example 1but replacing 4'-methoxy-5',6'-dihydro-2H-pyran with other 4-(lo-wer)alkoxy-5',6'-dihydro-2H-pyrans, e.g. 4'-ethoxy-5',6'-dihydro-ZH-pyran,the corresponding17f3-(4-loweralkoxytetrahydropyran-4-yloxy)-7B-rnethylandrost-4-en-3ones such as 175 (4' ethoxytetrahydropyran4-yloxy)-7[imethylandrost-4-en-3-one and the like are obtained.

EXAMPLE 4 A solution of 1 g. of l75-hydroxy-7B-methylestr-4-en- 3-0ne in40 ml. of benzene is distilled azeotropically to remove 3 ml. ofbenzene, thus removing moisture. A solution of 100 mg. p-toluenesulfonicacid in 100 ml. of

benzene is added to the solution, and then 1 ml. of 4-methoxy-S,6-dihydro-2H-pyran. The mixture is stirred for minutes at roomtemperature, bufi'ered with dry ethylamine and extracted withether-water. The ether phase is separated and evaporated to dryness, and200 mg. of the residue is applied to a preparative meter plate coatedwith silica gel. The plate is developed With hexaneethylacetate (2:1)containing a trace of pyridine and dried. The bands containing the17B-(5,6'-dihydro-2H- pyran-4'-yloxy)-7fi-methylestr-4-en-3-one and17fl-(4'- methoxytetrahydropyran-4-yloxy)-7B-methylestr-4-en 3- one areidentified (the latter is the least polar and travels further), removedand eluted. The solvent is dried to yield the respective, separatedcompounds as yellow amorphous compounds.

The invention claimed is:

1. A steroid ether represented by the formula:

R is hydrogen or methyl;

R is hydrogen or lower alkyl; and

R is 4'-(lower)a1koxytetrahydropyran-4'-yl or a 5',6'-

dihydro-2Hpyran-4'yl group.

2. Compounds of claim 1 wherein R is a 4-(lower)alkoxytetrahydropyran-4'-y1 group.

3. The compounds of claim 2 wherein R is a4'-methoxytetrahydropyran-4'-yl group.

4. A compound of claim 3 wherein R is hydrogen.

5. A compound of claim 4 wherein R is methyl.

6. A compound of claim 4 wherein R is hydrogen.

7. A compound of claim 3 wherein R is methyl.

8. A compound of claim 7 wherein R is methyl.

9. A compound of claim 7 wherein R is hydrogen.

10. A compound of claim 3 wherein R is ethyl.

11. A compound of claim 7 wherein R is methyl.

12. A compound of claim 7 wherein R is hydrogen.

wherein References Cited UNITED STATES PATENTS 3,213,086 10/1965 Cross260-23955 3,301,879 1/1967 Wettstein et al 260397.5 3,520,880 7/1970Cross et a1. 260 239.55 3,525,740 8/1970 Cross et a1 260-23955 HENRY A.FRENCH, Primary Examiner US. Cl. X.R. 260 999 U ITED STATES PATENTOFFICE 1 CERTIFICATE OF CORRECTION Patent No. 3,728, 3,36 l 3 DatedApril 17, 1973 n fl A.D. Cross and J.A. Edwards It is certifiedvthaterror appears in the above-identified patent and that said LettersPatent are hereby corrected as shown below:

Column 1, line 4, "4"yl" should read 4 '-yl Column 3, line 18, "l7B",l7ashould read 7B,l7oc.

Signed and sealed this 25th day of December 1973.

(SEAL) Attest:

EDWARD MTLETGHER R RENE n. TEGTMEYER Attesting Officer ActingCommissioner of Patents FDFIM PC4050 (10-69) USCOMM-DC seam-P09 A 1,1,5.GOVERNMENT [ITNTING QFFICE: 0-!4

